Bones provide rigid support for the body, maintain mineral homeostasis, and serve as the primary site for hematopoiesis. Bone homeostasis is maintained by the balanced action of osteoblasts and osteoclasts. Osteoclasts resorb bone and are derived from hematopoietic precursor cells. The formation and activation of osteoclasts are tightly regulated by osteoblasts, which provide two essential factors for osteoclastogenesis: TRANCE and M-CSF. Osteoblastic cells produce additional costimulators and inhibitory factors that further influence osteoblast-induced osteoclastogenesis. Many of the osteotropic factors modulating osteoclast differentiation exert their actions by regulating osteoblasts. This application stems in part from our attempt to provide insight into how osteotropic factors regulate osteoclast differentiation by modulating osteoblast activity. In our preliminary data, we have identified a member of the leucine rich repeat (LRR) proteins, LRRc17 (LRR containing 17), of previously unknown function, whose expression is highly enriched in osteoblasts. LRR motifs are found in various cytoplasmic, membrane and extracellular proteins (e.g., toll-like receptors). Although these proteins are associated with widely varied functions, a common property of LRR is involvement in protein-protein interaction. We show that LRRc17 mRNA expression in osteoblasts is suppressed in response to the pro-osteoclastogenic factor 1,25- dihydroxyvitamin D3 (1,25(OH)2D3), and enforced LRRc 17 expression in osteoblasts results in a failure of 1,25(OH)2D3 to induce osteoclast differentiation. These results strongly suggest that LRRc17 is an important negative regulator of osteoclast differentiation. Therefore, we propose to extend these studies of the regulation of osteoclast differentiation by LRRc17 by pursuing the following specific aims: (1) further characterization of the role of LRRc17 in osteoclast differentiation in vitro, (2) investigation of the role of LRRc17 as an inhibitor of bone resorption in vivo, and (3) investigation of the physiological role of LRRc17 in vivo. The knowledge gained from these studies will provide insights into how different molecules cooperate in inducing osteoclast differentiation, and how osteoclasts and osteoblasts communicate to regulate each other's function, which, in turn may help improve the treatment and prevention of osteoporosis and other bone diseases.